(1) Field of the Invention
This invention relates generally to peptide chains used to block binding sites on pathogens and more particularly to peptide chains used to block binding sites for Complement Factor H (CFH) on pathogens such as the Human Immunodeficiency Virus (HIV).
(2) Description of Related Art
Various pathogens, like HIV, have evolved the ability to escape from complement-mediated lysis. See, e.g., Marschang P. Sodroski J., Wurzner R. and Dierich M. P., "Decay-accelerating Factor (CD55) Protects Human Immunodeficiency Virus Type 1 From Inactivation by Human Complement," Eur. J. Immunol. 25: 285-90 (1995) and Horstmann, R. D., Sievertsen, H. J., Knobloch, J. and Fischetti, V. A., "Antiphagocytic Activity of Streptococcal M Protein: Selective Binding of Complement Control Protein Factor H," Proc. Nat'l. Acad. Sci. U.S.A. 85: 1657-1661 (1988). The complement system is part of the immune system. Its main functions are the opsonisation of micro-organisms to allow more efficient phagocytosis and complement-mediated lysis of pathogens. To turn down the activity of complement and to protect host cells from unspecific damage, regulators of complement activity (RCA's) are required. Among this family of negative regulators is CFH, a very abundant plasma protein. CFH has been shown to down-regulate the alternative pathway of complement activation by directly affecting the formation and stability of C3 and C5 convertase and by acting as a cofactor for the cleavage of C3b into its inactive form iC3b as described by Whaley, K. and Ruddy, S., "Modulation of the Alternative Complement Pathway by .beta.1H Globulin," J. Exp. Med. 144: 1147 (1976) and Pangburn, M. K., Schreiber and Eberland, H. J. Muller, "Human Complement C3b Inactivator: Isolation, Characterization and Demonstration of an Absolute Requirement for the Serum Protein .beta.1H for Cleavage of C3b and C4b in Solution," J. Exp. Med. 146:257 (1977). Responsible for these effects is a functional site located in the first 5 short consensus repeats (SCR 1-5) of CFH as described in Alsenz, J., Lambris, J. D., Schulz, T. F. and Dierich, M. P., "Localization of the Complement Component C3b-binding Site and the Cofactor Activity for Factor I in the 38-kDa Tryptic Fragment of Factor H," Biochem. J. 224: 389 (1984) and Gordon, D. L., Kaufman, R. M., Blackmore, T. K., Kwong, J. and Lublin, D. M., "Identification of Complement Regulatory Domains in Human Factor H," J. Immunol. 155: 348 (1995). An interaction site for polyanionic molecules has been mapped in SCR 13. Pangburn, M. K., Atkinson, M. A. and Meri, S., "Localization of the Heparin-binding Site on Complement Factor H," J. Biol. Chem. 266: 16847 (1991). For example, SCR 13 has been shown to bind streptococcal protein M and is responsible for protection of M+ strains from complement-mediated bactericidal activity. See Horstmann et al. article, above. Recently, additional binding regions for negatively-charged particles in SCR 7 have also been described. Blackmore, T. and Gordon, D., "SCR 7 is a Major Heparin/Sialic Acid Binding Site of Complement Factor H," J. Mol. Immunol. 33 (S1): 15 (1996). It is believed that SCR 7 is a potential binding site for host cells.
Applicants have recently shown the CFH interacts with specific sites on the envelope of HIV. Specifically, envelope glycoproteins, gp120 and gp41, have been demonstrated to be binding sites for CFH. See Stoiber, H., Ebenbichler, C., Schneider, R., Janatova, J. and Dierich, M. P., "Interaction of Several Complement Proteins with gp120 and gp41, the Two Envelope Glycoproteins of HIV-1," AIDS 9:19 (1995) and Pinter, C., Siccardi, A. G., Longhi, R. and Clivio, A., "Direct Interaction of Complement Factor H with the C1 Domain of HIV Type 1 Glycoprotein 120," AIDS Research & Human Retroviruses 11: 577 (1995). Incubation of free HIV or HIV-infected cells with sera that has been depleted of CFH (NHS.sup.CFH--) results in the complement-mediated virolysis of primary HIV isolates and the killing of HIV-infected cells. Re-titration of CFH to NHS.sup.CFH-- reconstitutes the resistance of HIV against complement-mediated destruction. See Stoiber, H., Pinter, C., Siccardi, A. G., Clivio, A. and Dierich, M. P., "Efficient Destruction of Human Immunodeficiency Virus in Human Serum by Inhibiting the Protective Action of Complement Factor H and Decay Accelerating Factor (DAF, CD55)," J. Exp. Med. 183: 307 (1996).
In addition, Applicants have shown that the antibody 2F5, described by Katinger et al. (See W095/07354 A1) interacts with a CFH binding site in gp41. From this information, the Applicants hypothesized that one of the HIV-neutralizing effects of this antibody is due to the inhibition of CFH interaction with gp41, resulting in complement-mediated lysis of the virus.
The present invention is based on the assumption that if the hypothesis described above is correct, it is not necessary to use an antibody for specifically blocking the binding sites on pathogens. Using a molecule which is able to block sites on pathogens which act as binding sites for CFH should have the same or even more promising effects.